tbuckley/cabot-search huggingface dataset:
BULK RNA-SEQ DECONVOLUTION OF IMAGE-LOCALIZED HIGGRADE GLIOMA BIOPSIES REVEALS MEANINGFUL CELLULAR STATES
Authors: Lee Curtin, Kamila Bond, Sebastian Velez, Andrea Hawkins-Daarud, Javier C Urcuyo, Gustavo De Leon, Jazlynn Langworthy, Christopher Sereduk, Kyle W Singleton, Pamela R Jackson, Chandan Krishna, Richard S Zimmerman, Devi P Patra, Bernard R Bendok, Kris A Smith, Peter Nakaji, Kliment Donev, Leslie C Baxter, Maciej M Mrugala, Osama Al-Dalahmah, Leland S Hu, Nhan L Tran, Peter Canoll, Kristin R Swanson
Journal: Neuro-Oncology (2023)

Abstract AIMS High-grade glioma continues to have dismal survival with current standard-of-care treatment, owing in part to its intra- and inter-patient heterogeneity. Typical diagnostic biopsies are taken from the dense tumor core to determine the presence of abnormal cells and the status of a few key genes (e.g. IDH1, MGMT). However, the tumor core is typically resected, leaving behind possibly genetically, transcriptomically and/or phenotypically distinct invasive margins that repopulate the disease. As these remaining populations are the ones ultimately being treated, it is important to know their compositional differences from the tumor core. We aim to identify the phenotypic niches defined by the relative composition of key cellular populations and understand their variation amongst patients. METHOD We have established an image-localized research biopsy study, that samples from both the invasive margin and tumor core. From this protocol, we currently have 202 samples from 58 patients with available bulk RNA-Seq, collected between Mayo Clinic and Barrow Neurological Institute. Using a single-cell reference dataset from our collaborators at Columbia University, we used CIBERSORTx, a deconvolution method, to predict relative abundances of 7 normal, 6 glioma, and 5 immune cell states for each sample. RESULTS We find that these cell state abundances connect to patient survival and show regional differences. For example, proneural glioma states were higher in invasive regions, whereas proliferative and mesenchymal states were higher in the tumor core. CONCLUSIONS Our analysis demonstrates a need to characterize the residual tissue following glioma resection to better understand the recurrent disease.
THREE FRACTION STEREOTACTIC RADIOTHERAPY (SRT) FOR VESTIBULAR SCHWANOMMA: THE WESSEX EXPERIENCE
Authors: Sean Main, Jeng Ching, Jasdeep Kaylan, Ramkumar Shanmugasundaram, Georges Sinclair, Enrico Clarke
Journal: Neuro-Oncology (2023)

Abstract AIMS Retrospective review of SRT for vestibular schwannoma. University Hospital Southampton treat tumour vol umes max 2.5cm in diameter without brainstem compression with 21Gy/3#. This reviews the experience of local control and toxicity profile in our centre and the impact of limiting dmax. METHOD Retrospective analysis of patients treated for radiologically diagnosed vestibular schwannoma from 2019 to present. Patient notes, audiograms, imaging and radiotherapy planning system were reviewed for data collection. No patients were removed from analysis due to missing data. RESULTS 36 patients have been treated with three fraction SRT. Median age 68 (47-83). PTV volume from 1.03cm3 to 5.52cm3 (median 2.37cm3). All patients have radiologically stable disease to date, with 14 patients (38.9%) having objective tumour response on imaging. 9 patients had serviceable hearing at baseline and 1 remained serviceable at follow up. 7 (19.4%) patients experienced treatment-related toxicity. 6 patients reported facial nerve toxicity in which 4 (66.7%) this was self-limiting with full recovery. 2 patients had persistent facial nerve symptoms (House-Brackmann score 2, and 3 respectively). Those with dmax &amp;lt;26Gy (n=15) experienced this less with only 1 patient experiencing facial nerve toxicity (House-Brackmann score 2). CONCLUSIONS Three fraction SRT provides excellent local control with high levels of objective radiological response in tumours up to 4cm3, however, long term follow-up is required. This treatment has acceptable toxicity with most symptoms resolving spontaneously. Permanent facial nerve toxicity was seen in 2 (5.6%) of patients. By limiting dmax to &amp;lt;26Gy the rate of facial nerve toxicity is reduced significantly.
Indoximod-based chemo-immunotherapy for pediatric brain tumors: A first-in-children phase I trial
Authors: Theodore S Johnson, Tobey J MacDonald, Rafal Pacholczyk, Dolly Aguilera, Ahmad Al-Basheer, Manish Bajaj, Pratiti Bandopadhayay, Zuzana Berrong, Eric Bouffet, Robert C Castellino, Kathleen Dorris, Bree R Eaton, Natia Esiashvili, Jason R Fangusaro, Nicholas Foreman, Diana Fridlyand, Cole Giller, Ian M Heger, Chenbin Huang, Nadja Kadom, Eugene P Kennedy, Neevika Manoharan, William Martin, Colleen McDonough, Rebecca S Parker, Vijay Ramaswamy, Eric Ring, Amyn Rojiani, Ramses F Sadek, Sarthak Satpathy, Matthew Schniederjan, Amy Smith, Christopher Smith, Beena E Thomas, Rachel Vaizer, Kee Kiat Yeo, Manoj K Bhasin, David H Munn
Journal: Neuro-Oncology (2023)

Abstract Background Recurrent brain tumors are the leading cause of cancer death in children. Indoleamine 2,3-dioxygenase (IDO) is a targetable metabolic checkpoint that, in preclinical models, inhibits anti-tumor immunity following chemotherapy. Methods We conducted a phase I trial (NCT02502708) of the oral IDO-pathway inhibitor indoximod in children with recurrent brain tumors or newly diagnosed diffuse intrinsic pontine glioma (DIPG). Separate dose-finding arms were performed for indoximod in combination with oral temozolomide (200 mg/m2/day x 5 days in 28-day cycles), or with palliative conformal radiation. Blood samples were collected at baseline and monthly for single-cell RNA-sequencing with paired single-cell T cell receptor sequencing. Results Eighty-one patients were treated with indoximod-based combination therapy. Median follow-up was 52 months (range 39–77 months). Maximum tolerated dose was not reached, and the pediatric dose of indoximod was determined as 19.2 mg/kg/dose, twice daily. Median overall survival was 13.3 months (n = 68, range 0.2–62.7) for all patients with recurrent disease and 14.4 months (n = 13, range 4.7–29.7) for DIPG. The subset of n = 26 patients who showed evidence of objective response (even a partial or mixed response) had over 3-fold longer median OS (25.2 months, range 5.4–61.9, p = 0.006) compared to n = 37 nonresponders (7.3 months, range 0.2–62.7). Four patients remain free of active disease longer than 36 months. Single-cell sequencing confirmed emergence of new circulating CD8 T cell clonotypes with late effector phenotype. Conclusions Indoximod was well tolerated and could be safely combined with chemotherapy and radiation. Encouraging preliminary evidence of efficacy supports advancing to Phase II/III trials for pediatric brain tumors.
SIX YEARS OF NEURO-NAVIGATION ASSISTED BRAIN TUMOUR SURGERY: PROGRESS AND CHALLENGES
Authors: Ugochukwu Ugwuanyi, Morayo Salawu, Obinna Ayogu, Paul Jubrin
Journal: Neuro-Oncology (2023)

Abstract AIMS To report a six-year experience with computerized neuro-navigation assistance in our neuro-oncology surgeries and services. METHOD Retrospective review of all consecutive cases involving computer-assisted neuro-navigation diagnostic and resective brain tumour operation over a six-year period (January 2016-December 2021). Main study parameters: Clinical diagnostic procedures, operations, histological diagnosis, adjuvant treatments. Data were analysed using simple descriptive statistics, and results were presented accordingly. RESULTS Total number of cases 111, Males 70 and Females 41 (M: F = 1.7:1). Age ranges from 8 months to 80 years. The commonest presentation was headache, nausea, and vomiting. Pre-op diagnosis: Intra axial tumours 70/111 (63%), Extra axial tumours 41/111 (36%). Operations: Resection/Debulking of tumour 86/111(77,4%), with complete EOR of 65/86 (75%). Diagnostic Biopsy 68/111(61%) with target precision of 100%. Common Histology were Gliomas 50/111(45%), Meningiomas 41/111 (36.9%), and Metastatic 15/111 (13.5%). Adjuvant treatments and follow-ups were advised accordingly. CONCLUSIONS With computerized neuro-navigation assistance, a wider spectrum of brain tumours were more confidently operated, and adjuvant treatments were easily deployed in line with a precise histological diagnosis for improved neuro-oncology services. But this success was at a huge cost of adopting measures to overcome some inevitable challenges.
QUANTIFYING THE NEED FOR A BEST SUPPORTIVE CARE CLINIC
Authors: Marwan Al-Munaer, Sam Holman, Emma Wilby, Andrew Brodbelt
Journal: Neuro-Oncology (2023)

Abstract AIMS Patients newly diagnosed with high-grade primary brain tumour and poor performance status discussed in the Multidisciplinary team (MDT) may not be felt to benefit from active treatment and their uptake in clinic is poor. We aimed to explore the volume of patients not being treated in our region, their survival rates, and the reasons for the limited requests for clinical review. METHOD Data was obtained from medical records of identified patients from April 2021 to April 2022. This included demographics, presentation, diagnosis date, clinic visits, and date of death. RESULTS 78 patients were referred for suspected high-grade primary brain tumours and selected for best supportive care by the MDT. Only 73 (64% male) were diagnosed radiologically with a high-grade primary tumour and the rest were excluded. Median age was 79 years (range 74 – 84). The commonest presenting symptoms were confusion (53%), falls (29%), and dysphasia (25%). Median survival time after diagnostic scan was 67 days (range 34 – 107). Survival rates at 1, 3, 6, and 12 months were 82%, 33%, 8%, and 1%, respectively. 28 patients (38%) were seen in clinic. 13 had been provided with the option to attend by letter. The median duration from referral to clinic was 9 days (range 7 – 14). CONCLUSIONS Only a third of non-treatable patients with newly diagnosed high-grade primary brain tumours are being seen in the clinic. Communication between the MDT and the patient offering this service is poor. Longer term survivors suggest an incorrect diagnosis who may benefit from further review.
TITLE THE TEENAGE AND YOUNG ADULT (TYA) POPULATION (16-24YO) BENEfiT FROM HAVING SPECIALIST NURSE INPUT
Authors: Sarah Hedges, Jessica La, Charlotte Robinson, Victoria Hurwitz, Ellie Kostick, Aeron Suarez, Nicola Harding, Renata Fukuthi, Lucy Brazil, Katia Cikurel, Omar Al-Salihi, Angela Swampillai, Kazumi Chia, Vishal Manik, Ranjeev Bhangoo, Keyoumars Ashkan, Jose Pedro Lavrador, Francesco Vergani, Richard Gullan, Bassel Zebian, Cristina Bleil
Journal: Neuro-Oncology (2023)

Abstract AIMS The aim of this review is to analyse the need for a specialist nurse role for the TYA patients. Having a new dedicated TYA developmental role implemented can help by identifying areas for improvement from the wider team to ensure optimal support for patient group. METHOD Clinic attendance over a 1-year period has been measured. Looking specifically at patients who did not attend (DNA) appointments in a monthly TYA joint surgical and oncology clinic. We have evidence engaging this age group with the creation of a nurse led weekly telephone clinic for TYA patients and have looked at the trajectory of attendees throughout the year. RESULTS To date, nurse led clinic has had 107 individual bookings between August 2022 and February 2023. This is a devoted telephone clinic to provide holistic care. CONCLUSIONS There were 107 nurse lead telephone clinic appointments that were booked and attended by this patient group over 6-month period. This was protected time for which the nurse specialist was able to explore patients individual care needs in a holistic way. Figures for holistic needs assessment (eHNA) are yet to be collated; but the TYA group are now routinely offered eHNA to ensure a holistic care approach and support to this vulnerable patient group.
SYSTEMATIC IDENTIfiCATION OF CONTEXT-DEPENDENT GENE-ESSENTIALITY IN GLIOBLASTOMA: THE GBM-CODE PLATFORM
Authors: Mitchell Foster, Ailith Ewing, Margaret Frame, Paul Brennan, Ava Khamseh, Sjoerd Beentjes, Neil Carragher, Colin Semple
Journal: Neuro-Oncology (2023)

Abstract AIMS Glioblastoma (GBM) is a heterogeneous and aggressive brain tumour that is invariably fatal despite maximal treatment. GBM-relevant ‘biomarkers’ (such as known driver-mutations or cell-states) could be used to stratify patients for treatments. However, pairing biomarkers with appropriate therapeutic ‘targets’ is challenging. If a gene is more essential in GBM cells which contain such a biomarker, inhibiting the gene product may be therapeutically useful in GBM tumours where that biomarker is present. METHOD We describe a novel computational tool which distils new translational insights from existing disparate large- scale biological data (genomics, transcriptomics and functional genomics data from 60 distinct patient-derived, IDH-wildtype, adult GBM cell lines) using Targeted Learning (a subfield of mathematics and causal machine learning) to systematically identify context-dependent gene essentiality in Glioblastoma (GBM-CoDE). RESULTS We derived multiple target-biomarker pair hypotheses, two of which (WWTR1 is more essential in EGFR- mutated/amplified GBM, and VRK1 is more essential in VRK2-methylated GBM) have recently been published by external groups, implying that our additional novel findings may be valid. We developed an interactive plat- form to make our findings accessible to other researchers to prioritise pairs for experimental validation and subsequent translation. CONCLUSIONS GBM-CoDE represents a potent new approach to solving the problem of developing patient-tailored therapeutics in GBM, made possible with recent innovations in computational biology. While the majority of these target- biomarker hypotheses have yet to be experimentally validated, our results may in time accelerate effective translation to biomarker stratified clinical trials in GBM. Our method is translatable to other cancers of unmet need.
DO GENOMIC ALTERATIONS INflUENCE THE DEVELOPMENT OF BRAIN METASTASES IN ADVANCED AND METASTATIC NON-SMALL CELL LUNG CANCER? A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Conor Gillespie, Mohammad Mustafa, George Richardson, Ali Alam, Keng Siang Lee, David Hughes, Carles Escriu, Rasheed Zakaria
Journal: Neuro-Oncology (2023)

Abstract AIMS Establish prevalence at diagnosis, and incidence of BM in patients with advanced and metastatic non-small cell lung cancer (NSCLC), stratified by genomic alterations. METHOD A systematic review and meta-analysis was conducted in accordance with PRISMA guidelines (PROSPERO ID CRD42022315915). Three databases were searched (Search date 30th April 2022). Prevalence at diagnosis, and per-patient year incidence of brain metastases were obtained, including patients with EGFR, ALK, KRAS, ROS1, RET, and other genomic alterations. Pooled incidence rates were calculated using random effects models. RESULTS Of 960 articles identified, 65 were included (24,784 patients). The combined BM prevalence at diagnosis was 28.6% (45 studies, 95% Confidence Interval [CI] 26.1-31.0). Median follow-up was 24 months (Interquartile range [IQR] 16-36 months). The combined incidence of BM development was 10.8% per year (40 studies, 95% CI 9.2- 12.6). The per-year incidence of new BM was 15.6%/year in the EGFR +ve group (16 studies, 95% CI 11.4-21.2), 17.0% in the ALK+ve group (7 studies, 95% CI 11.3-25.8), 9.8% in the KRAS +ve group (4 studies, 95% CI 5.5-17.5), 12.5% in the ROS1 +ve group (3 studies, 95% CI 5.7-27.6), and 11.8% in the RET +ve group (2 studies, 95% CI 8.0-17.5). Combined overall prevalence was 55.0% (21 studies, IQR 44.2-67.8). CONCLUSIONS This systematic review indicates a high rate of brain metastases in NSCLC and is the first and only study to describe incidence, stratified by genomic alterations. This will have a major clinical impact by stratifying brain imaging at staging and follow-up by patient subgroup, particularly in ALK and EGFR mutations.
RADIOMICS TO PREDICT THE RESPONSE OF BRAIN METASTASES TO STEREOTACTIC RADIOTHERAPY
Authors: Hamoun Rozati, Elsa Angelini, Matthew Williams
Journal: Neuro-Oncology (2023)

Abstract AIMS Radiomics converts routinely obtained medical imaging into mineable, high-dimensionality data. We assessed its utility for incorporation into a multivariate model to predict the likelihood of response of brain metastases (BMs) to stereotactic radiotherapy (SRT). METHOD Patients treated with SRT over a ten-year period for BMs at three tertiary centres were retrospectively analyzed. SRT planning MRI scans were pre-processed, and radiomic features were extracted from each BM using PyRadiomics software. Follow up scans were analyzed for response and quantified by a modification of the Response Assessment in Neuro-Oncology Brain Metastases criteria. A radiomic signature predictive of BM response was created by a stepwise process involving correlation coeffcients and a binary least absolute shrinkage and se- lection operator regression analysis. A clinical predictive multivariate model for predicting response was com- pared against a combination clinical/radiomic model by McFadden’s pseudo-R-squared test. RESULTS 520 patients were included contributing a total of 1891 BMs. 1131 radiomic features were extracted from each BM. 12 features were used to construct a radiomic signature. Mean dose and BM volume were independent predictors of response in both the clinical and radiomics models. The radiomic signature was an independent prognostic predictor for response in the radiomic model (HR=1.095-1.231). Goodness of fit for predicting response was greater in the radiomics model (McFadden’s pseudo-R-squared score 0.243 vs 0.211), and statistically significant by likelihood ratio test (p=0.021). CONCLUSIONS This multi-centre retrospective analysis created a unique radiomic signature for predicting BM response to SRT and is the first study to incorporate clinical factors. A prospective validation study is planned.
IN VITRO MODELLING OF CROSSTALK BETWEEN PAEDIATRIC CEREBELLAR TUMOURS AND HEALTHY BRAIN TISSUE IN THE POST-SURGICAL MICROENVIRONMENT
Authors: Harry Porter, Phoebe McCrorie, Cara Moloney, Pamela Collier, Nicola Croxall, David Onion, Anna Kotowska, David Scurr, Mohammed Diksin, Richard Grundy, Ruman Rahman
Journal: Neuro-Oncology (2023)

Abstract AIMS Atypical Teratoid Rhabdoid Tumours (ATRT) and Medulloblastoma are embryonal brain tumours arising in the cerebellum. Many in vitro models of paediatric brain tumours fail to recapitulate key pathophysiological characteristics. We aim to address this gap by developing a bespoke model incorporating cellular and acellular aspects of the TME. METHOD Cerebellar tissue from a healthy human autopsy donor brain was decellularized to form cerebellar ECM and incorporated into a “blank slate” hydrogel. Spheroid-forming multi-well plates were coated with the hydrogel and used to culture patient-derived Medulloblastoma and ATRT cells in co-culture with primary human cerebellar astrocytes. RESULTS Tissue decellularization and retention of ECM components was demonstrated using colorimetric assays and Orbitrap Secondary Ion Mass Spectrometry. Biocompatibility of the ECM hydrogel was shown in 2D and 3D culture conditions using the CellTiter-Glo® 3D cell viability assay. Furthermore, the size and morphology of spheroids grown on the hydrogel was characterised using a high-throughput imaging and analysis methodology. Cell lines were labelled to facilitate discrimination between tumour cells and astrocytes. Optical sections of co-culture spheroids generated using confocal microscopy showed cell-cell contact between tumour cells and astrocytes. Finally, co-culture spheroids were separated by fluorescence activated cell sorting to facilitate downstream analyses on individual cell types. CONCLUSIONS This work presents a highly characterised model of medulloblastoma and ATRT interactions with healthy brain tissue, mimicking the immediate post-surgical microenvironment. Future work will utilise transcriptomics to assess the tumour-astrocyte crosstalk modelled using this system.
IDENTIFYING ROLE OF YB1 AND NPM1 AS PART OF HISTONE 3 MUTANT PROTEIN INTERACTOME, IN H3 MUTATED PHGG
Authors: Tarak Cambampaty, Lucy Barrow, Robert Layfield, Farhana Haque
Journal: Neuro-Oncology (2023)

Abstract AIMS Paediatric high-grade gliomas (pHGG) are the leading cause of childhood cancer deaths, accounting for over 40% of deaths in the UK. pHGG tumours harbour histone H3 mutations, defining 50% of pHGG cases. Studies show prominent mutations as being H3.3K27M and H3.3G34R/V. Our previous research has identified unique and common interacting binding partners of H3-G34R and H3-G34V mutant proteins. Among these we have focused on YB-1 and Nucleophosmin (NPM1). YB-1 is multifunctional transcription factor and a well-known oncogenic protein. NPM1 is a molecular chaperone and frequently over- expressed in cancer as well. Our aim is to analyse the role of YB-1 and NPM1 in H3 mutated pHGG, in order to identify targeted therapeutic option for these diffcult to treat tumours. METHOD Further data analyses of mass spectrometric proteomic data were performed. Subsequently, H3 mutated glioma cell lines, and control H3 wild type pHGG cells were cultured and then subjected to proteomic analyses. A comparative immunofluorescence and microscopy, and western blot analyses were performed to investigate the role of YB-1 and NPM-1. RESULTS Results verified the proteomic data and further showed altered protein expression of YB-1 and altered localization of protein NPM1 in H3 mutated pHGG. CONCLUSIONS Results of the study support that YB-1 and NPM1 are important interacting proteins in H3G34-mutated pHGGs and can be explored as therapeutic targets in H3 mutated pHGG.
DEVELOPMENT OF GLIEXP; A HIGH-THROUGHPUT EX VIVO DRUG SCREENING PLATFORM FOR GLIOBLASTOMA
Authors: Hannah Gagg, Sophie Williams, Ola Rominiyi, Sarah Danson, Spencer Collis, Greg Wells
Journal: Neuro-Oncology (2023)

Abstract AIMS With diminishing returns and common clinical failure rates from traditional preclinical and animal-based drug discovery strategies, emphasis is being placed on alternative drug discovery platforms, such as ex vivo approaches. Such approaches represent a departure from both preclinical animal-based models and more traditional clinical-based strategies and aim to address intra/inter-patient variability at an earlier stage of drug discovery. Additionally, they could also offer precise treatment stratification for patients within a week of surgery to direct a tailored treatment course. One tumour group that could significantly benefit from such ex vivo approaches are high-grade gliomas, which exhibit extensive heterogeneity, cellular plasticity and therapy- resistant glioma stem cell (GSC) niches, and where historic preclinical models have failed to generate new therapies leading to 50-year stagnant dire survival rates of around 15 months post-diagnosis. METHOD We have developed and optimized a high-throughput ex vivo drug screening platform; GliExP, which maintains GSC populations using immediately dissociated fresh surgical tissue. RESULTS As a proof-of-concept for GliExP, we have optimized standard-of-care chemoradiotherapy responses which can correctly predict MGMT status based on Temozolomide sensitivity. We have screened 30+ small molecule therapeutics and preclinical compounds against 18 different patient’s tumours, including multi-region spatial het- erogeneity sampling from several individual tumours. Drug responses are further correlated to transcriptomic and genetic profiles. CONCLUSIONS Our data provides a strong basis to build upon GliExP to incorporate combination-based oncology therapeutics in tandem with standard-of-care therapies as an important preclinical model to triage experimental therapeutics for clinical translation, delivering rapid identification of effective treatment strategies for individual gliomas.